Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Image 1.

Objective Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the leading cause of hospitalization and death in patients with chronic obstructive pulmonary disease (COPD). Exploring the prognostic factors of AECOPD patients will assist in optimizing treatment strategies and standardizing disease management. Methods This study retrospectively collected the clinical data of 664 patients with AECOPD admitted to the Respiratory Department of Dongzhimen Hospital of Beijing University of Chinese Medicine from January 2013 to September 2019. The 3-year survival rate and treatment of the patients were investigated. According to whether the patients died,they were divided into a non-survivors group and a survivors group,and clinical data such as basic information,comorbidities,and auxiliary examination results were compared between the two groups. Incorporating clinical experience of researchers and previous research evidence,a secondary screening of variables was conducted to ultimately determine the covariates to be included in the multifactorial Cox proportional hazards regression model,and the factors affecting the 3-year survival rate of the patients were analyzed. Results A total of 664 cases were included in this study,including 362 males and 302 females,with an average age of (77.25±6.89) years old. The 3-year all-cause mortality rate of older hospitalized patients with AECOPD was 20.48％(136 patients). Older age (HR:1.071,95％CI:1.040-1.102,P<0.001);smoking history (HR:1.788,95％CI:1.173-2.723,P=0.007);Charlson comorbidity index (HR:1.209,95％CI:1.029-1.421,P=0.022);lower arterial partial pressure of oxygen (HR:1.014,95％CI:1.006-1.022,P<0.001);higher brain natriuretic peptide(HR:1.001,95％CI:1.000-1.001,P=0.025);cor pulmonale(HR:1.896,95％CI:1.235-2.908,P=0.004);respiratory failure (HR:2.437,95％CI:1.378-4.311,P=0.003);TCM syndrome differentiation elements,including kidney (HR:1.639,95％CI:1.055-2.546,P=0.028) and fluid retention (HR:2.512,95％CI:1.653-3.816,P<0.001),were independent risk factors for 3-year all-cause death of older hospitalized patients with AECOPD. Long-term regular use of bronchiectasis (HR:0.474,95％CI:0.324-0.695,P<0.001) was an independent protective factor for 3-year all-cause death. Conclusion The 3-year survival rate of elderly hospitalized patients with AECOPD is relatively low,with the TCM syndrome elements manifested as lung-kidney qi deficiency,yang deficiency with water retention,and blood stasis obstruction. Patients with moderate to severe impairment of lung function due to COPD have an increased risk of death within 3 years. Therefore,for such patients,nourishing lung-kidney qi,resolving phlegm and water retention,activating blood circulation to remove blood stasis and dredging collaterals,combined with regular use of bronchodilators,may help improve their 3-year survival rate.

{L-End}Objective To analyze the effects of night shift work and overweight/obesity on blood pressure of workers in chemical fiber industry. {L-End}Methods A total of 1 004 workers of a chemical fiber factory were selected as the study subjects using convenient sampling method, and their blood pressure and body mass index were measured. Multiple linear regression model was used to analyze the relationship between night shift work and blood pressure, and multiple logistic regression was used to assess the independent impact and combined impact of night shifts and overweight/obesity on the risk of hypertension. {L-End}Results Compared with the non-night shift workers, the prevalence of hypertension in night shift workers was increased (5.3% vs 13.0%, P<0.05), with elevated systolic and diastolic blood pressure (both P<0.05). The results of multiple linear regression analysis showed that the systolic blood pressure and diastolic blood pressure of the night shift workers were higher than those of the non-night shift workers (both P<0.05), and the systolic blood pressure and diastolic blood pressure of overweight/obesity workers were higher than those of non-overweight/obesity workers (both P<0.01). The results of multiple logistic regression analysis showed that the risk of hypertension in night shift workers and overweight/obesity workers was higher than that in non-night shift workers and non-overweight/obesity workers [odds ratio (OR) and 95% confidence interval (CI) were 2.49 (1.04-5.99) and 2.65 (1.77-3.95), both P<0.05]. Night shift work and overweight/obesity showed a synergistic effect on blood pressure of workers. Compared to non-overweight/obesity non-night shift workers, overweight/obesity night shift workers had a higher risk of hypertension (OR=4.93, 95%CI: 1.70-14.29, P<0.01). {L-End}Conclusion Night shift work could lead to elevated blood pressure in workers in the chemical fiber industry, which is a potential risk factor for hypertension. The synergistic effect of night shift work and overweight/obesity may contribute to the increased risk of hypertension.

Objective:To explore the change in cerebral blood flow when healthy subjects swallow hot and ice water, and to verify the sensitivity of functional near-infrared spectroscopy (fNIRS) in identifying liquid temperatures while swallowing as a basis for applying it in diagnosis and intervention.Methods:Sixteen healthy subjects swallowed hot and ice water in randomized order while the process was recorded using fNIRS. The activation at rest and when swallowing hot and ice water was compared pairwise.Results:Compared with the resting state, 19 channels were activated during the swallowing of the hot and ice water. The common activated areas were S1, M1, PMC, SMA, Wernicke′s area, the somatosensory association cortex, the visual association cortex and the frontal eye field. However, the dorsal lateral prefrontal cortex was activated only when swallowing hot water, and the subcentral area was activated only when swallowing ice water. The SMA and PMC were significantly more activated when swallowing hot water than ice water.Conclusions:Multiple brain regions are activated and participate in regulating swallowing. The PMC and SMA areas can distinguish hot water from ice water swallowing.

Objective:To seek any correlation between cortical activity and the swallowing of dysphagia patients with infratentorial stroke, and to observe any effect of three-needle acupuncture of the tongue on such activity.Methods:Thirty infratentorial stroke survivors with dysphagia were randomly divided into a tongue three-needle group and a sham acupuncture group, each of 15. Functional near-infrared spectroscopy was used to monitor changes in the concentration of oxygenated hemoglobin (ΔHbO 2) at rest, during acupuncture (or sham acupuncture), during real or sham electro-acupuncture, and at rest after the acupuncture or sham acupuncture treatment. The Modified Rankin Scale, a Penetration-Aspiration Scale (PAS), and the Functional Oral Intake Scale were employed to assess overall functional disability and the swallowing of both groups. Results:At rest the average ΔHbO 2 concentrations recorded in the left primary motor cortex, the left dorsolateral prefrontal cortex and the left premotor cortex in both groups were positively correlated with the PAS scores. During the acupuncture ΔHbO 2 concentration in the right inferior frontal gyrus and the left middle temporal gyrus increased significantly in the tongue three-needle group. It decreased significantly in the left somatosensory cortex and the left primary motor cortex. Conclusion:Three-needle acupuncture of the tongue induces changes in cortical activity in infratentorial stroke survivors with dysphagia, suggesting a potential technique for improving disordered swallowing.

Objective:To analyze the epidemiological characteristics and genotypes of human rhinovirus (HRV) in patients with upper respiratory tract infection in Qingdao in the winter of 2020.Methods:Throat swab samples were collected from 101 patients with upper respiratory tract infection in Qingdao from November 2020 to January 2021. Quantitative PCR was used to detect 15 common respiratory viruses in the samples. HRV-positive samples were further analyzed with RT-PCR to amplify and sequence HRV VP4/VP2 gene. A phylogenetic tree was constructed based on the sequencing results and homology analysis was conducted.Results:Six common respiratory viruses were detected in the 101 patients. Thirty-four cases (34/101, 33.66%) were single pathogen infection and two cases were multiple infection (2/101, 1.98%). The positive rate of HRV was the highest (21.78%, 22/101). Twenty HRV VP4/VP2 sequences were successfully amplified. Phylogenetic analysis showed that there were 16 strains of HRV-A subtype and four strains of HRV-C subtype and 14 serotypes were involved.Conclusions:HRV was one of the leading viral pathogens causing upper respiratory tract infection in Qingdao in the winter of 2020 and the predominant subtype was HRV-A.

Objective:To Isolate and identify human rhinovirus (HRV) in hospitalized children with pneumonia in Qingdao in 2020.Methods:A total of 98 throat swab samples were collected from hospitalized children with pneumonia in 2020. Common respiratory viruses were screened through RT-qPCR. The HRV positive samples were inoculated into H1-HeLa cells. Viruses with typical cytopathic effect (CPE) were identified by HRV specific RT-PCR. Subsequently, sequences of HRV-VP4/VP2 gene were used to construct phylogenetic trees and analyze homology with sequences of reference strains through MEGA software.Results:Among 98 hospitalized children with pneumonia, 11 samples were HRV positive in 98 throat swab samples. After the typical CPE appeared in HeLa cells, two strains of HRV were identified by specific RT-PCR. The HRV-A28 and HRV-A58 were confirmed by comparison and analysis of VP4/VP2 sequence. Phylogenetic tree found that the isolated HRV-A28 strain was genetically close to strains of Singapore in 2011, of Tunisia in 2017, and Kenya in 2017. The isolated HRV-A58 strain was genetically close to the strains of Australia in 2009, Venezuela in 2011, Mongolia in 2011, and the United States in 2014.Conclusions:The HRV-A28 and HRV-A58 strains were isolated from the throat swabs of children patients with pneumonia in Qingdao.

Background::Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy. Methods::Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification. Results::A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1. Conclusions::The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.

Objective:To investigate the regulation of intestinal microbiota by Roux-en-Y gastric bypass (RYGB) on patients with obesity or obesity combined with diabetes.Methods:The retrospective and descriptive study was conducted. The stool samples before and after surgery and clinical data of 20 patients with obesity, including 9 simple obesity cases and 11 obesity combined with diabetes cases, who underwent RYGB in the First Affiliated Hospital of Ji′nan University from July 2016 to August 2017 were collected. There were 11 males and 9 females, aged (33±11)years. Observation indicators: (1) changes in composition and structure of intestinal microflora; (2) changes of intestinal microflora in simple obesity patients after operation; (3) changes of intestinal microflora in obesity combined with diabetes patients after operation. Follow up was conducted using telephone interview or outpatient examinations to detect the body mass, the application of antimicrobial agent and the blood glucose control of patients. According to the unified training points, the stool samples were collected and stored into the DNA stabilizer, and then conducted to laboratory analysis within 45 hours. The follow up was up to November 2018. Measurement data with normal distribution were represented as Mean± SD, and independent-samples t test was used for inter-group comparison and paired-samples t test was used for intra-group comparison. Measurement data with skewed distribution were represented as M( Q1, Q3), and Wilcoxon signed rank test of two independent samples was used for inter-group comparison. Count data were described as absolute numbers, and the chi-square test, ANOSIM analysis, linear discriminant (LEfSe) analysis and the Metastats analysis were used for inter-group comparison. Results:(1) Changes in composition and structure of intestinal microflora. The Shannon index of α diversity of preoperative intestinal microflora in simple obesity patients and obesity combined with diabetes patients was 4.37±0.69 and 4.47±0.85, respectively, showing no significant difference between them ( t=0.28, P>0.05). Results of preoperative LEfSe analysis showed that there were differences in the bacterial abundance of Firmicutes and Bacteroidea between simple obesity patients and obesity combined with diabetes patients. The abundances of Parasutterella in simple obesity patients and obesity combined with diabetes patients was 0.000 113 0(0, 0.004 378 2) and 0.008 464 0(0.001 325 7, 0.034 983 1), respectively, showing a significant difference between them ( Z=2.12, P<0.05). Results of preoperative PCoA analysis showed that the contribution rates of principal component 1, principal component 2 and principal component 3 were 24.98%, 22.24% and 16.33% in simple obesity patients and obesity combined with diabetes patients and results of ANOSIM comparison showed that there was no significant difference in preoperative intestinal microflora between them ( r=?0.11, P>0.05). The Shannon index of α diversity of postoperative intestinal microflora in simple obesity patients and obesity combined with diabetes patients was 4.60±0.65 and 4.66±0.40, respectively, showing no significant difference between them ( t=0.24, P>0.05). Results of postoperative LEfSe analysis showed that there were differences in the bacterial abundance of Bacteroidea, Proteus and Firmicutes between simple obesity patients and obesity combined with diabetes patients. The abundances of Morganella and Coprococcus_2 in simple obesity patients and obesity combined with diabetes patients were 0.000 192 0(0.000 011 9,0.001 569 0), 0(0,0) and 0(0,0), 0.000 054 1(0,0.000 419 0), showing significant differences between them ( Z=2.70, 2.29, P<0.05). (2) Changes of intestinal microflora in simple obesity patients after operation. There were 10 genera of bacteria of intestinal bacteria changing after surgery, including 7 species of bacteria increasing in the Firmicutes and the Proteobacteria as Veillonella, Morganella, Granulicatella, Aeromonas, Streptococcus, Rothia and Megasphaera and the bacteria decreasing in the Firmicutes and the Actinobacteria as Ruminococcus_torques_group, Romboutsia and Erysipelo-trichaceae_UCG-003. Results of LEfSe analysis showed that the bacteria significantly enriched in simple obesity patients before surgery were Ruminococcus_torques_group, Romboutsia and Erysipelotri-chaceae_UCG-003, belonging to Firmicutes, and the bacteria significantly enriched in simple obesity patients after surgery were Rothia, Granulicatella, Enterococcus, Streptococcus, Megasphaera, Veillonella, A eromonas and Morganella, belonging to Actinobacteria, Firmicutes and Proteobacteria. (3) Changes of intestinal microflora in obesity combined with diabetes patients after operation. There were 16 bacteria of intestinal bacteria increasing after surgery, including Streptococcus, Veillonella, Haemophilus, Pluralibacter, Gemella, Lachnospiraceae_NC2004_group, Granulicatella,Aeromonas, uncultured_ bacterium_f_ Saccharimonadaceae, R uminiclostridium_9, Butyricicoccus, Fusobacterium, Anaerotruncus, Fusicateni-bacter, Klebsiella and E ubacterium_eligens_group, which belonged to the Firmicutes and the Proteo-bacteria. Results of LEfSe analysis showed that the bacteria significantly enriched in obesity combined with diabetes patients before surgery were Fusicatenibacter, Tyzzerella_3 and Butyricicoccus, belonging to the Firmicutes, and the bacteria significantly enriched in obesity combined with diabetes patients after surgery were Gemella, Granulicatella, Enterococcus, Streptococcus, Lachnospiraceae_NC2004_group, Eubacterium_eligens_group, Anaerotruncus, Ruminiclostridium_9, Anaeroglobus, Veillonella, Fusobacterium, uncultured_bacterium_f_Saccharimonadaceae, Aeromonas, Klebsiella, Pluralibacter, Proteus and Haemophilus, belonging to the Firmicutes and the Proteobacteria. Conclusions:RYGB can significantly increases the intestinal microflora abundance in simple obesity patients and obesity combined with diabetes patients. The two types of patients have specific changes in intestinal microflora at the genus level.